The dynamic nature of bone as seen in its ability to model and remodel in response to externally applied forces is of critical importance to the practice of orthopedic surgery. Mechanical factors are important regulators of bone mass in health as well as in disease states such as osteoporosis. Understanding how bone cells respond to mechanical perturbation is a key step towards understanding and treating these disorders as well as such problems as fracture healing, disuse osteoporosis and stress shielding around orthopedic implants. The long-term objective of this proposal is to assist the applicant in becoming an independent clinician scientist by developing an independent research program studying the molecular basis of mechanotransduction in a mentored environment. The applicant has received clinical and research training, having completed a residency in orthopedic surgery and a Ph.D. in biochemistry. The University of Michigan Medical Center provides a research environment with intellectual and technical support and a record of fostering new careers. Additionally, the proposed mentors have expertise in bone biology, mechanotransduction and in mentoring developing scientists. The response of bone to mechanical stimuli involves the concerted action of bone forming cells, osteoblasts and bone resorbing cells, osteoclasts. Recent studies have identified LRP5 as an important regulator of bone mass that works at the level of bone formation by the osteoblast. It also appears to be important in the response of bone to mechanical load. LRP5 is a key component in the Wnt signal transduction pathway. This proposal will seek to elucidate the interaction between LRP5 and mechanical load- isLRP5funtion regulated by load or visa versa. Load will be applied to osteoblasts in culture. Experiments will be performed to address 1) the effect of load on signaling through the Wnt pathway, and 2) the effect of loss of function of LRP5 on the global response of cells to mechanical load. Lastly, the requirement for LRP in the adaptation response of bone to mechanical load in vivo will be determined. These studies should not only further the understanding of mechanotransduction in bone, but also serve as the basis for future studies by the applicant as an independent scientist.